EP2941252A2 - Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies - Google Patents

Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies

Info

Publication number
EP2941252A2
EP2941252A2 EP14735304.9A EP14735304A EP2941252A2 EP 2941252 A2 EP2941252 A2 EP 2941252A2 EP 14735304 A EP14735304 A EP 14735304A EP 2941252 A2 EP2941252 A2 EP 2941252A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently
compound
docosa
therapeutic agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14735304.9A
Other languages
German (de)
English (en)
Other versions
EP2941252A4 (fr
Inventor
Jean E. Bemis
Chi B. Vu
Jill C. Milne
Michael R. Jirousek
Joanne DONOVAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astria Therapeutics Inc
Original Assignee
Catabasis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Catabasis Pharmaceuticals Inc filed Critical Catabasis Pharmaceuticals Inc
Publication of EP2941252A2 publication Critical patent/EP2941252A2/fr
Publication of EP2941252A4 publication Critical patent/EP2941252A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to fatty acid niacin conjugates; compositions comprising an effective amount of a fatty acid niacin conjugate; methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate, and methods for treating or preventing a metabolic disease comprising the administration of an effective amount of a fatty acid niacin conjugate and another therapeutic agent.
  • Oily cold water fish such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Both niacin and marine omega-3 fatty acids have been shown to reduce cardiovascular disease, coronary heart disease, atherosclerosis and reduce mortality in patients with dyslipidemia, hypercholesterolemia, or Type 2 diabetes, and metabolic disease.
  • Niacin at high dose has been shown to improve very low-density lipoprotein ("VLDL”) levels through lowering Apolipoprotein B (“ApoB”) and raising high density lipoprotein (“HDL”) through increasing Apolipoprotein Al (“ApoAl”) in the liver.
  • VLDL very low-density lipoprotein
  • ApoB Apolipoprotein B
  • HDL high density lipoprotein
  • ApoAl Apolipoprotein Al
  • Niacin can also inhibit diacylglycerol acyltransferase-2, a key enzyme for TG synthesis (Kamanna, V. S.; Kashyap, M. L. Am. J. Cardiol. 2008, 101 (8A), 20B-26B).
  • niacin has many actions outside of the liver that detract from its therapeutic utility. The most common side effect of niacin is flushing, which can limit the dose a patient can tolerate. Flushing is thought to occur through the GPR109 receptor
  • Omega-3 fatty acids have been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to be improved in overweight hypertensive subjects through treatment with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as part of the dietary supplement portion of therapy used to treat dyslipidemia.
  • the invention is based in part on the discovery of fatty acid niacin conjugates and their demonstrated effects in achieving improved treatment that cannot be achieved by administering niacin or fatty acids alone or in combination.
  • the fatty acid niacin conjugates provided herein were designed to be stable in the plasma and when present in cells and targeted tissues, and without wishing to be bound to any particular theory, intracellular enzymes hydrolyze the fatty acid niacin conjugates releasing the individual components (i.e. niacin and omega-3 fatty acid).
  • enzymatic hydrolysis are described in WO 2012/129112 the disclosure of which is incorporated by reference herein for all purposes.
  • Non limiting examples of metabolic diseases include hypertriglyceridemia, severe hypertriglyceridemia, hypercholesterolemia, familial hypercholesterolemia, elevated cholesterol caused by a genetic condition, fatty liver disease, nonalcoholic fatty liver disease (NFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia, mixed dyslipidemia, atherosclerosis, coronary heart disease, Type 2 diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, or cardiovascular disease.
  • NFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the invention is also based in part on the suprising discovery that fatty acid niacin conjugates are useful in treating hyperlipoproteinemia.
  • hyperlipoproteinemia There are five types of hyperlipoproteinemia (types I through V) and these are further classified according to the Fredrikson classification, based on the pattern of lipoproteins on electrophoresis or ultracentrifugation.
  • Type I hyperlipoproteinemia has three subtypes: Type la (also called Buerger-Gruetz syndrome or familial hyperchylomicronemia), Type lb (also called familial apoprotein CII deficiency) and Type Ic.
  • Type I hyperlipoproteinemia Due to defects in either decreased in lipoprotein lipase (LPL), altered ApoC2 or LPL inhibitor in blood, all three subtypes of Type I hyperlipoproteinemia share the same characteristic increase in chylomicrons.
  • the frequency of occurrence for Type I hyperlipoproteinemia is 1 in 1,000,000 and thus far no drug therapy is available and treatment has consisted only of diet. Because of the ability of fatty acid niacin conjugates in affecting postprandial lipids, it can be especially useful in treating Type I hyperlipoproteinemia.
  • Type II hyperlipoproteinemia has two subtypes: Type Ila (also called familial hypercholesterolemia) is characterized by an elevated level of low-density lipoprotein (LDL); and Type lib (also called familial combined hyperlipidemia) is characterized by an elevated level of LDL and very- low density lipoprotein (VLDL).
  • Type III hyperlipoproteinemia also called familial dysbetalipoprotememia
  • Type IV hyperlipoproteinemia also called familial hypertriglyceridemia
  • Type V hyperlipoproteinemia is characterized by an elevated level of VLDL and chylomicrons.
  • Type V hyperlipoproteinemia thus far has not been adequate with using just niacin or fibrate. Because of the ability of fatty acid niacin conjugates in affecting postprandial lipids, it can be especially useful in treating Type V hyperlipoproteinemia.
  • the compounds of the invention can be used in combination with other therapies that have been shown to be clinically effective in treating metabolic diseases.
  • the biological effect produced by using a combination of a fatty acid niacin conjugate with another metabolic disease agent is synergistic.
  • Wi and W 2 are each independently null, S, NH, NR, or Wi and W 2 can be taken together can form an imidazolidine or piperazine group; each a, b, c and d is independently -H, -D, -CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(0)OR, or -O-Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q is independently 0, 1 or 2; each L is independently null, -0-, -S-, -S(O)-, -S(0) 2 -, -S-S-, -(Ci-C 6 alkyl)-, -(C 3 - C 6 cycloalkyl)-, a heterocycle, a
  • Re is independently -H, -D, -C 1 -C4 alkyl, -halogen, cyano, oxo, thiooxo, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)C C 4 alkyl, -C C 3 alkene, -C C 3 alkyne, -C(0)Ci-C 4 alkyl, -NH 2 , -NH(Ci-C 3 alkyl), -N(Ci-C 3 alkyl) 2 , -NH(C(0)Ci-C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(Ci-C 3 alkyl), -S(0)Ci-C 3 alkyl, -S(0) 2 Ci-C 3 alkyl;
  • R 5 is each independently selected from the group consisting of -H, -D, -CI, -F, -CN, -NH 2 , -NH(Ci-C 3 alkyl), -N(C C 3 alkyl) 2 , -NH(C(0)C C 3 alkyl), -N(C(0)C C 3
  • each r is independently 2, 3, or each s is independently 3, 5, or each t is independently 0 or 1 ; each v is independently 1, 2, or Ri and R 2 are each independently hydrogen, deuterium, -C 1 -C4 alkyl, -halogen, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)Ci-C 4 alkyl, -C1-C3 alkene, -C1-C3 alkyne, -C(0)Ci-C 4 alkyl, -NH 2 , -NH(Ci-C 3 alkyl), -N(Ci-C 3 alkyl) 2 , -NH(C(0)Ci-C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(Ci-C 3 alkyl), -S(0)Ci-C 3 alkyl, -S(0) 2 Ci
  • any one or more of H may be substituted with a deuterium. It is also understood in Formula I that a methyl substituent can be substituted with a Ci-C 6 alkyl.
  • compositions comprising at least one fatty acid niacin conjugate.
  • the invention also includes pharmaceutical compositions that comprise an effective amount of a fatty acid niacin conjugate and a pharmaceutically acceptable carrier.
  • the compositions are useful for treating or preventing a metabolic disease.
  • the invention includes a fatty acid niacin conjugate provided as a pharmaceutically acceptable prodrug, hydrate, salt, , enantiomer, stereoisomer, or mixtures thereof.
  • Also described are methods of treating a metabolic disease comprising administering to a patient in need thereof an effective amount of a compound of Formula I
  • Wi and W 2 are each independently null, S, NH, NR, or Wi and W 2 can be taken together can form an imidazolidine or piperazine group; each a, b, c and d is independently -H, -D, -CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(0)OR, or -O-Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q is independently 0, 1 or 2; each L is independently null, -0-, -S-, -S(O)-, -S(0) 2 -, -S-S-, -(Ci-C 6 alkyl)-, -(C 3 - C 6 cycloalkyl)-, a heterocycle, a heteroaryl,
  • Re is independently -H, -D, -C 1 -C4 alkyl, -halogen, cyano, oxo, thiooxo, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)Ci-C 4 alkyl, -C 1 -C 3 alkene, -C 1 -C 3 alkyne, -C(0)C C 4 alkyl, -NH 2 , -NH(C C 3 alkyl), -N(C C 3 alkyl) 2 , -NH(C(0)C C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(Ci-C 3 alkyl), -S(0)Ci-C 3 alkyl, -S(0) 2 Ci-C 3 alkyl;
  • R 5 is each independently selected from the group consisting of -H, -D, -CI, -F, -CN, -NH 2 , -NH(Ci-C 3 alkyl), -N(C C 3 alkyl) 2 , -NH(C(0)C C 3 alkyl), -N(C(0)C C 3 alkyl) 2 ,-C(0)H, -C(0)Ci-C 3 alkyl, -C(0)OCi-C 3 alkyl, -C(0)NH 2 , -C(0)NH(Ci-C 3 alkyl), -C(0)N(Ci-C 3 alkyl) 2 , -Ci-C 3 alkyl, -0-Ci-C 3 alkyl, -S(0)Ci-C 3 alkyl and -S(0) 2 Ci-C 3 alkyl; each g is independently 2, 3 or 4; each h is independently 1, 2, 3 or 4; m is 0, 1, 2, or 3; if m is more than 1, then
  • Ri and R 2 are each independently hydrogen, deuterium, -C 1 -C4 alkyl, -halogen, -OH, -C(0)Ci-C 4 alkyl, -O-aryl, -O-benzyl, -OC(0)Ci-C 4 alkyl, -C1-C3 alkene, -Ci-C 3 alkyne, -C(0)Ci-C 4 alkyl, -NH 2 , -NH(Ci-C 3 alkyl), -N(Ci-C 3 alkyl) 2 , -NH(C(0)Ci-C 3 alkyl), -N(C(0)Ci-C 3 alkyl) 2 , -SH, -S(Ci-C 3 alkyl), -S(0)Ci-C 3 alkyl, -S(0) 2 Ci-C 3 alkyl; and each R is independently -H, -Ci-C 3 alkyl, phenyl or straight or branched C 1
  • the metabolic disease is selected from the group consisting of hypertriglyceridemia, severe hypertriglyceridemia, hypercholesterolemia, familial hypercholesterolemia, elevated cholesterol caused by a genetic condition, fatty liver disease, nonalcoholic fatty liver disease (NFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia, mixed dyslipidemia, atherosclerosis, coronary heart disease, Type 2 diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, or cardiovascular disease.
  • methods of treating a metabolic disease comprising administering to a patient in need thereof an effective amount of a compound of Formula I and another therapeutic agent.
  • the therapeutic agent is a statin.
  • the statin is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, and the combination of ezetimibe/simvastatin (Vytorin®).
  • the therapeutic agent is a fibrate or hypolipidemic agent.
  • the fibrate or hypolipidemic agent is selected from the group consisting ofacifran, acipimox, beclobrate, bezafibrate, binifibrate, ciprofibrate, clofibrate, colesevelam, gemfibrozil, fenofibrate, melinamide, and ronafibrate.
  • the therapeutic agent lowers proprotein convertase subtilisin/kexin type 9.
  • the therapeutic agent that lowers proprotein convertase subtilisin/kexin type 9 is selected from a PCSK9 monoclonal antibody, a biologic agent, a small interfering RNA (siRNA) and a gene silencing oligonucleotide.
  • the PCSK9 monoclonal antibody is selected from REGN727 and AMG 145.
  • the small interfering RNA (siRNA) is ALN-PCS.
  • the therapeutic agent is a microsomal triglyceride transfer protein (MTP) inhibitor.
  • the microsomal triglyceride transfer protein (MTP) inhibitor is selected from lomitapide, implitapide, CP-346086, SLx-4090, and AS 1552133.
  • the therapeutic agent treats NASH or NAFLD.
  • the therapeutic agent that treats NASH or NAFLD is cysteamine.
  • the therapeutic agent that treats NASH or NAFLD is an FXR (farnesoid X receptor) agonist.
  • the FXR (farnesoid X receptor) agonist is obeticholic acid.
  • the therapeutic agent is an apolipoprotein B synthesis inhibitor.
  • the apolipoprotein B synthesis inhibitor is selected from mipomersen, a biologic agent, a small interfering RNA (siRNA) and a gene silencing oligonucleotide.
  • the therapeutic agent is a CETP (cholesteryl transfer protein) inhibitor.
  • the CETP (cholesteryl transfer protein) inhibitor is selected from dalcetrapib, evacetrapib, anacetrapib and torcetrapib.
  • the therapeutic agent is a lipid lowering agent.
  • the lipid lowering agent is selected from agents that raise ApoA-I, HM74a agonists, squalene synthetase inhibitors, and lipoprotein-associated phospholipase A2 inhibitors.
  • the therapeutic agent is an anti-diabetic agent.
  • the anti-diabetic agent is selected from acarbose, epalrestat, exenatide, glimepiride, liraglutide, metformin, miglitol, mitiglinide, nateglinide, pioglitazone, pramlintide, repaglinide, rosiglitazone, tolrestat, troglitazone, and voglibose.
  • the anti-diabetic agent is a DPP-IV (dipeptidyl peptidase- 4) inhibitor.
  • the DPP-IV (dipeptidyl peptidase-4) inhibitor is selected from sitagliptin, saxagliptin, vildagliptin, linagliptin, dutogliptin, gemigliptin and alogliptin.
  • the therapeutic agent is an antihypertensive agent.
  • the antihypertensive agent is selected from alacepril, alfuzosin, aliskiren, amlodipine besylate, amosulalol, aranidipine, arotinolol HCl, azelnidipine, barnidipine hydrochloride, benazepril hydrochloride, benidipine hydrochloride, betaxolol HCl, bevantolol HCl, bisoprolol fumarate, bopindolol, bosentan, budralazine, bunazosin HCl, candesartan cilexetil, captopril, carvedilol, celiprolol HCl, cicletanine, cilazapril, cinildipine, clevidipine, delapril, dilevalol, doxazosin mesylate, efonidipine, enalapril
  • Figure 1 is a depiction of the effect of compound 1-7 on ApoB secretion in HepG2 cells.
  • Figure 2 is a depiction of the effect of fatty acid niacin conjugates on SREBP-lc target genes.
  • Figure 3 is a depiction of the plasma cholesterol of ApoE*3 Leiden mice after 2 weeks of treatment.
  • Figure 4 is a depiction of the plasma cholesterol of ApoE*3 Leiden mice after 4 weeks of treatment.
  • Figure 5 is a depiction of the plasma triglyceride of ApoE*3 Leiden mice after 4 weeks of treatment.
  • Figure 6 is a depiction of the triglyceride levels across four treatment groups immediately following an NIH high fat meal.
  • Figure 7 is a depiction of the triglyceride levels across four treatment groups 2 hours following an NIH high fat meal.
  • Figure 8 is a depiction of the triglyceride levels across four treatment groups 4 hours following an NIH high fat meal.
  • Figure 9 is a depiction of the reduction in liver weight gain by coadministration of Compound 1-8 in mice on a high fat diet treated with lOmg/kg Lomitapide.
  • Figure 10 is a depiction of the reduction in liver weight gain by coadministration of Compound 1-8 in mice on a high fat diet treated with either 1 or 3 mg/kg Lomitapide.
  • Metabolic diseases are a wide variety of medical disorders that interfere with a subject's metabolism. Metabolism is the process a subject's body uses to transform food into energy. Metabolism in a subject with a metabolic disease is disrupted in some way. The fatty acid niacin conjugates possess the ability to treat or prevent metabolic diseases.
  • the fatty acid niacin conjugates have been designed to bring together niacin analogs and omega-3 fatty acids into a single molecular conjugate.
  • the activity of the fatty acid niacin conjugates is substantially greater than the sum of the individual components of the molecular conjugate, suggesting that the activity induced by the fatty acid niacin conjugates is synergistic.
  • fatty acid niacin conjugates includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the fatty acid niacin conjugates described herein.
  • the articles "a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted.
  • C 1 -C 3 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms.
  • Examples of a C 1 -C 3 alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl.
  • C 1 -C 4 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms.
  • Examples of a C 1 -C 4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.
  • C 1 -C 5 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms.
  • Examples of a C 1 -C 5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
  • Ci-C 6 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms.
  • Examples of a Ci-C 6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.
  • cycloalkyl refers to a cyclic hydrocarbon containing 3-6 carbon atoms.
  • examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is understood that any of the substitutable hydrogens on an alkyl and cycloalkyl can be substituted with halogen, C 1 -C3 alkyl, hydroxyl, alkoxy and cyano groups.
  • heterocycle refers to a cyclic hydrocarbon containing 3-6 atoms wherein at least one of the atoms is an O, N, or S.
  • heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.
  • any one of the side chains of the naturally occurring amino acids means a side chain of any one of the following amino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine, and Tyrosine.
  • fatty acid as used herein means an omega-3 fatty acid and fatty acids that are metabolized in vivo to omega-3 fatty acids.
  • Non- limiting examples of fatty acids are all- cz ' s-7,10,13-hexadecatrienoic acid, a-linolenic acid (ALA or a/7-cz ' s-9,12,15-octadecatrienoic acid), stearidonic acid (STD or a/7-cz ' s-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis- 11,14, 17-eicosatrienoic acid), eicosatetraenoic acid (ETA or all-cis- 8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA or all-cis-5,%,11,14,17- eicos
  • niacin as used herein means the molecule known as niacin.
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus, and the terms “subject” and “patient” are used interchangeably herein.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a fatty acid niacin conjugate and a pharmaceutically acceptable carrier.
  • the invention includes a fatty acid niacin conjugate provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.
  • Representative "pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
  • metabolic disease refers to disorders, diseases and syndromes involving dyslipidemia, and the terms metabolic disorder, metabolic disease, and metabolic syndrome are used interchangeably herein.
  • an "effective amount" when used in connection with a fatty acid niacin conjugate is an amount effective for treating or preventing a metabolic disease.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • treating refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug conjugate or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means ⁇ e.g., by hydrolysis) to a fatty acid niacin conjugate.
  • Boc and BOC are tert-butoxycarbonyl
  • Boc 2 0 is di-tert-butyl dicarbonate
  • BSA bovine serum albumin
  • CDI is 1 , ⁇ -carbonyldiimidazole
  • DCC is N,N'-dicyclohexylcarbodiimide
  • DIEA is N,N-diisopropylethylamine
  • DMAP is 4-dimethylaminopyridine
  • DMEM is Dulbecco's Modified Eagle Medium
  • DMF is N,N-dimethylformamide
  • DOSS sodium dioctyl sulfosuccinate
  • EDC and EDCI are l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • ELISA is enzyme-linked immunosorbent assay
  • EtOAc is ethyl acetate
  • FBS fetal bovine bovine serum albumin
  • CDI
  • the present invention provides fatty acid niacin conjugates according to Formula I:
  • R n is
  • one Z is
  • one Z is and r is 7.
  • one Z is and s is 3.
  • one Z is and s is 5.
  • one Z is and s is 6.
  • one Z is and v is 1.
  • one Z is and v is 2.
  • one Z is and v is 6.
  • one Z is and s is 3.
  • one Z is
  • one Z is
  • Wi is NH.
  • W 2 is NH
  • Wi is null.
  • W 2 is null.
  • Wi and W 2 are each NH.
  • Wi and W 2 are each null.
  • Wi and W 2 are each NR, and at least one of R is C3 ⁇ 4.
  • m is 0.
  • m is 1.
  • n is 2.
  • L is -S- or -S-S-.
  • L is -0-.
  • L is -C(O)-.
  • L is heteroaryl
  • L is heterocycle
  • L is [0088] In some embodiments, L is
  • L is N
  • L is N
  • L is N
  • L is
  • L is ⁇ ⁇ ( CH2 ) m ⁇ wherein m is 2.
  • L is ⁇ ⁇ ⁇ CH2 ⁇ m wherein m is 3.
  • L i .s L i .s
  • L is N
  • L is N
  • L is N
  • L is
  • L is [0102] In other embodiments, one of n, o, p, and q is 1.
  • two of n, o, p, and q are each 1.
  • n, o, p, and q are each 1.
  • n, o, p, and q are each 1.
  • one d is C(0)OR.
  • r is 2 and s is 6.
  • r is 3 and s is 5.
  • t is 1.
  • Wi and W 2 are each NH, m is 0, n, and o are each 1, and p and q are each 0.
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is O.
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and
  • L is -S-S-.
  • Wi and W 2 are each NH, m is 1, n and o are each 0, p and q are each 1 , and L is
  • Wi and W 2 are each NH, m is 1, k is O, n and o are each 0, p and q are each 1 , and L is
  • Wi and W 2 are each NH, m is 1, n and o are each 1, p and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, k is 0, n is 1, o, p and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1 , n, o, and p are each 0, and q is 1 , and L is
  • Wi and W 2 are each NH, m is 1, k is 1, n, o, and p are each 0, and q is 1 , and L is
  • Wi and W 2 are each NH, m is 1, n is 1, and o, p, and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, k is 1, o, p, and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and
  • Wi and W 2 are each NH, m is 0, k is 1, o and p are each 1, and q is 0.
  • Wi and W 2 are each NH, m is 0, n, o, p, and q are each 1.
  • Wi and W 2 are each NH, m is 0, n and o are each 1, p and q are each 0, and each a is CH 3 .
  • Wi and W 2 are each NH, m is 0, n and o are each 1, p and q are each 0, and each b is CH 3 .
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, R 3 is H, and L is [0129] In some embodiments, Wi and W 2 are each NH, m is 1, n, p and q are each 1, and o is 2, R-3 is H, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p are each 1, and q is 2, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, and q are each 1, and L is
  • Wi and W 2 are each NH, m is 1, n and p are each 1, and o and q are each 0, and L is -C(O)-.
  • Wi and W 2 are each NH, m is 1, n and p are each 1, and o, and q are each 0, and L is
  • Wi and W 2 are each NH, m is 1, n, o, p, q are each 1, and L is
  • Wi and W 2 are each NH, m is 1 , n, o, p , and q are each 1 , h is 1 , and L is [0136] In some embodiments, Wi and W 2 are each NH, m is 1, n, o, p , and q are each 1, and L is-S-.
  • Wi and W 2 are each NH, m is 1, n, o, p are each 0, q is 1, one d is -CH 3 , and L is
  • Wi and W 2 are each NH, m is 2, n, o, p, and q are each 0, one L is
  • m is 0, n, o, p, and q are each 0, and Wi and W 2 are taken together to form an optionally substituted piperazine group.
  • m is 1, n, o, p, and q are each 0, Wi and W 2 are each null, and L is
  • m is 1, n and p are each 1, o and q are each 0, Wi and W 2 are each NH, and L is C 3 -C 6 cycloalkyl.
  • m is 1, n is 1, o, p, and q are each 0, Wi and W 2 are each NH, and L is C 3 -C 6 cycloalkyl.
  • m is 1, n, o, p, are each 0, q is 1, Wi and W 2 are each NH, and L is C 3 -C 6 cycloalkyl.
  • m is 1 , n, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1 , n o, p, and q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1 , n o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1 , n o, p, and q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1
  • n is 1, o, p, and q are each 0, Wi is NH
  • W 2 is null, and
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and L is [0150] In some embodiments, m is 1 , n, o, p, and q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1 , n, o, p, and q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1
  • n is 1, o, p, and q are each 0, Wi is NH
  • W 2 is null, and
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and L is
  • m is 1
  • n is 1, o, p, and q are each 0, Wi is NH
  • W 2 is null
  • L is
  • m is 1, n, o, p, are each 0, q is 1, Wi is null, W 2 is NH, and L is [0156] In some embodiments, m is 1, n, o, p, q are each 0, Wi and W 2 is null, and L is
  • m is 1, n, o, p, q are each 0, Wi and W 2 is null, and L is
  • m is 1, n, o, p, q are each 0, Wi is NH, W 2 is null, and L is
  • m is 1, n, o, p, q are each 0, Wi is null, W 2 is NH, and L is
  • m is 1, n, o, p, are each 0, q is 1, Wi and W 2 are each and NH, is null, L is
  • m is 1, n, o, p, are each 0, q is 1, Wi and W 2 are each NH, is null, and L is a heteroaryl.
  • r is 2
  • s is 6
  • t is 1.
  • r is 3, s is 5 and t is 1.
  • any one or more of H may be substituted with a deuterium. It is also understood in Formula I that a methyl substituent can be substituted with a Ci-C 6 alkyl. [0165] In other illustrative embodiments, compounds of Formula I are as set forth below:
  • the invention also includes methods for treating metabolic diseases such as the treatment or prevention of metabolic diseases including atherosclerosis, dyslipidemia, coronary heart disease, hypercholesterolemia, Type 2 diabetes, elevated cholesterol, metabolic syndrome and cardiovascular disease.
  • metabolic diseases including atherosclerosis, dyslipidemia, coronary heart disease, hypercholesterolemia, Type 2 diabetes, elevated cholesterol, metabolic syndrome and cardiovascular disease.
  • the method comprises contacting a cell with a fatty acid niacin conjugate in an amount sufficient to decrease the release of triglycerides or VLDL or LDL or cause an increase in reverse cholesterol transport or increase HDL concentrations.
  • Also provided in the invention is a method for inhibiting, preventing, or treating a metabolic disease, or symptoms of a metabolic disease, in a subject.
  • disorders include, but are not limited to atherosclerosis, dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmias, low HDL levels, high LDL levels, sudden death, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, carotid atherosclerosis, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease, arterial occlusive diseases, cerebral arteriosclerosis, cerebrovascular disorders, myocardial ischemia, and diabetic autonomic neuropathy
  • the present invention provides a method of treating hyperlipoproteinemia comprising administering to a patient in need thereof, a molecular conjugate which comprises a niacin and a fatty acid covalently linked, wherein the fatty acid is selected from the group consisting of omega-3 fatty acids and fatty acids that are metabolized in vivo to omega-3 fatty acids.
  • the conjugate comprises at least one amide and the conjugate is capable of hydrolysis to produce free niacin and free fatty acid.
  • the invention also includes methods for treating metabolic diseases such as hyperlipoproteinemia.
  • hyperlipoproteinemia There are five types of hyperlipoproteinemia (types I through V) and these are further classified according to the Fredrikson classification, based on the pattern of lipoproteins on electrophoresis or ultracentrifugation.
  • Type I hyperlipoproteinemia has three subtypes: Type la (also called Buerger-Gruetz syndrome or familial hyperchylomicronemia), Type lb (also called familial apoprotein CII deficiency) and Type Ic.
  • Type I hyperlipoproteinemia Due to defects in either decreased in lipoprotein lipase (LPL), altered ApoC2 or LPL inhibitor in blood, all three subtypes of Type I hyperlipoproteinemia share the same characteristic increase in chylomicrons.
  • the frequency of occurrence for Type I hyperlipoproteinemia is 1 in 1,000,000 and thus far treatment has consisted mainly of diet. Because of the ability of fatty acid niacin conjugates in affecting postprandial lipids, it can be especially useful in treating Type I hyperlipoproteinemia.
  • Type II hyperlipoproteinemia has two subtypes: Type Ila (also called familial hypercholesterolemia) is characterized by an elevated level of low-density lipoprotein (LDL); and Type lib (also called familial combined hyperlipidemia) is characterized by an elevated level of LDL and very-low density lipoprotein (VLDL).
  • Type III hyperlipoproteinemia also called familial dysbetalipoproteinemia
  • Type IV hyperlipoproteinemia also called familial hypertriglyceridemia
  • Type V hyperlipoproteinemia is characterized by an elevated level of VLDL and chylomicrons.
  • Type V hyperlipoproteinemia thus far has not been adequate with using just niacin or fibrate. Because of the ability of fatty acid niacin conjugates in affecting postprandial lipids, it can be especially useful in treating Type V hyperlipoproteinemia.
  • the subject is administered an effective amount of a fatty acid niacin conjugate.
  • the invention also includes pharmaceutical compositions useful for treating or preventing a metabolic disease, or for inhibiting a metabolic disease, or more than one of these activities.
  • the compositions can be suitable for internal use and comprise an effective amount of a fatty acid niacin conjugate and a pharmaceutically acceptable carrier.
  • the fatty acid niacin conjugates are especially useful in that they demonstrate very low peripheral toxicity or no peripheral toxicity.
  • the fatty acid niacin conjugates can each be administered in amounts that are sufficient to treat or prevent a metabolic disease or prevent the development thereof in subjects.
  • Administration of the fatty acid niacin conjugates can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time -release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time -release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a fatty acid niacin conjugate and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or conjugates thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or poly
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the fatty acid niacin conjugate is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the fatty acid niacin conjugates.
  • the fatty acid niacin conjugates can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the fatty acid niacin conjugates can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564, the contents of which are herein incorporated by reference in their entirety.
  • Fatty acid niacin conjugates can also be delivered by the use of monoclonal antibodies as individual carriers to which the fatty acid niacin conjugates are coupled.
  • the fatty acid niacin conjugates can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysme substituted with palmitoyl residues.
  • fatty acid niacin conjugates can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • fatty acid niacin conjugates are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 80 %, from about 5 % to about 60 %, or from about 1 % to about 20 % of the fatty acid niacin conjugate by weight or volume.
  • the dosage regimen utilizing the fatty acid niacin conjugate is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular fatty acid niacin conjugate employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the present invention when used for the indicated effects, range from about 20 mg to about 5,000 mg of the fatty acid niacin conjugate per day.
  • Compositions for in vivo or in vitro use can contain about 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the fatty acid niacin conjugate.
  • the compositions are in the form of a tablet that can be scored.
  • Effective plasma levels of the fatty acid niacin conjugate can range from about 0.002 mg to about 100 mg per kg of body weight per day.
  • Appropriate dosages of the fatty acid niacin conjugates can be determined as set forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226.
  • Fatty acid niacin conjugates can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, fatty acid niacin conjugates can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the fatty acid niacin conjugate ranges from about 0.1 % to about 15 %, w/w or w/v.
  • Fatty acid niacin conjugates may also be administered with other therapeutic agents such as cholesterol-lowering agents, fibrates and hypolipidemic agents, anti-diabetic agents, agents used to treat NASH and NAFLD, lipid-lowering agents and antihypertensive agents.
  • the other therapeutic agent is a cholesterol-lowering agents.
  • Non limiting examples of cholesterol-lowering agents are atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, and the combination of ezetimibe/simvastatin (Vytorin®).
  • the other therapeutic agent is a fibrate or hypolipidemic agent.
  • fibrates or hypolipidemic agents are acifran, acipimox, beclobrate, bezafibrate, binifibrate, ciprofibrate, clofibrate, colesevelam, gemfibrozil, fenofibrate, melinamide, and ronafibrate.
  • the other therapeutic agent is an agent that can lower PCSK9 (proprotein convertase subtilisin/kexin type 9).
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • Non- limiting examples include a PCSK9 monoclonal antibody, a biologic agent, a small interfering RNA (siRNA) and a gene silencing oligonucleotide.
  • the other therapeutic agent is a microsomal triglyceride transfer protein (MTP) inhibitor.
  • MTP inhibitors include lomitapide, implitapide, CP-346086, SLx-4090, and AS1552133.
  • the other therapeutic agent is one that can be used to treat NASH or NAFLD.
  • agents that can be used to treat NASH or NAFLD include cysteamine, and an FXR (farnesoid X receptor) agonist such as obeticholic acid(a bile acid analog).
  • the other therapeutic agent is an apolipoprotein B synthesis inhibitor.
  • apolipoprotein B synthesis inhibitors include mipomersen, a biologic agent, a small interfering RNA (siRNA) and a gene silencing oligonucleotide.
  • the other therapeutic agent is a CETP (cholesteryl transfer protein) inhibitor.
  • CETP inhibitors include dalcetrapib, evacetrapib, anacetrapib and torcetrapib.
  • the other therapeutic agent is a lipid lowering agent.
  • lipid lowering agents include agents that raise ApoA-I, HM74a agonists, squalene synthetase inhibitors, and lipoprotein-associated phospholipase A2 inhibitors.
  • the other therapeutic agent is an Anti-diabetic agent.
  • anti-diabetic agents are acarbose, epalrestat, exenatide, glimepiride, liraglutide, metformin, miglitol, mitiglinide, nateglinide, pioglitazone, pramlintide, repaglinide, rosiglitazone, tolrestat, troglitazone, and voglibose.
  • the other therapeutic agent is a DPP-IV (dipeptidyl peptidase- 4) inhibitor as anti-diabetic agent.
  • Non-limiting examples of DPP-IV inhibitors as antidiabetic agents are sitagliptin, saxagliptin, vildagliptin, linagliptin, dutogliptin, gemigliptin and alogliptin.
  • the other therapeutic agent is an antihypertensive agents.
  • antihypertensive agents include alacepril, alfuzosin, aliskiren, amlodipine besylate, amosulalol, aranidipine, arotinolol HCl, azelnidipine, barnidipine hydrochloride, benazepril hydrochloride, benidipine hydrochloride, betaxolol HCl, bevantolol HCl, bisoprolol fumarate, bopindolol, bosentan, budralazine, bunazosin HCl, candesartan cilexetil, captopril, carvedilol, celiprolol HCl, cicletanine, cilazapril, cinildipine, clevidipine, delapril, dilevalol, doxazos
  • the mono-BOC protected amine of the formula B can be obtained from commercial sources or prepared according to the procedures outlined in Krapcho et al. Synthetic Communications 1990, 20, 2559-2564.
  • Compound A can be amidated with the amine B using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane to produce the coupled compound C.
  • Activation of compound C with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of formula D affords compounds of the formula E.
  • R, r, and s are as defined above.
  • the acylated amine of the formula F can be prepared using the procedures outlined in Andruszkiewicz et al. Synthetic Communications 2008, 38, 905-913.
  • Compound A can be amidated with the amine F using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane to produce the coupled compound G.
  • Activation of compound G with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of formula D affords compounds of the formula H.
  • Activation of compound J with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of formula D affords compounds of the formula K.
  • Hydrolysis of the ester under basic conditions such as NaOH or LiOH produces the corresponding acid, which can be coupled with glycidol to afford compounds of the formula L.
  • the amine M can be prepared according to the procedures outlined in Dahan et al. J. Org. Chem. 2007, 72, 2289-2296.
  • Compound A can be coupled with the amine M using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 C1 2 or dioxane to produce the coupled compound N.
  • Activation of compound N with a coupling agent such as HATU in the presence of an amine such as DIEA followed by addition of a fatty acid of formula D affords compounds of the formula O.
  • Compound A can be amidated with the commercially available amine P using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound Q.
  • the BOC group in compound Q can be removed with acids such as TFA or HC1 in a solvent such as CH 2 CI 2 or dioxane and the resulting amine can be coupled with a fatty acid of formula D using a coupling agent such as HATU in the presence of an amine such as DIEA to afford compounds of the formula R.
  • the sulfur group in formula Q can be oxidized to the corresponding sulfoxide or sulfone using an oxidizing agent such as H 2 0 2 or oxone.
  • the amine T can be prepared from the commercially available diamine according to the procedures outlined in Dahan et al. J. Org. Chem. 2007, 72, 2289-2296.
  • Compound A can be amidated with the amine T using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound U.
  • the BOC group of compound U can be removed with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane and the resulting amine can be coupled with a fatty acid of formula D using HATU in the presence of an amine such as DIEA to afford compounds of the formula V.
  • the hydroxyl group in compound U can be further acylated or converted to an amino group by standard mesylation chemistry followed by displacement with sodium azide and hydrogenation over a catalyst such as Pd/C.
  • the amine can be further acylated or alkylated, followed by the removal of the BOC group.
  • the resulting amine can be coupled with a fatty acid of the formula D to afford compounds of the formula W.
  • Compound A can be amidated with the commercially available amine X using a coupling reagent such as DCC, CDI, EDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP to afford compound Y.
  • a coupling reagent such as DCC, CDI, EDC
  • a tertiary amine base and/or catalyst e.g., DMAP
  • the BOC group in compound Y can be removed with acids such as TFA or HCl in a solvent such as CH 2 CI 2 or dioxane.
  • the resulting amine can be coupled with a fatty acid of the formula D using a coupling agent such as HATU in the presence of an amine such as DIEA to afford compounds of the formula Z.
  • Compound A can be amidated with the commercially available cysteine methyl ester using a coupling reagent such as DCC, CDI, EDC, or optionally with a tertiary amine base and/or catalyst, e.g., DMAP, to afford compound AA.
  • the commercially available maleimide conjugate BB can be coupled with a fatty acid of the formula D using a coupling agent such as HATU or EDCI to afford compounds of the formula CC.
  • Compound AA can be coupled to compounds of the formula CC in a solvent such as acetonitrile to afford compounds of the formula DD.
  • R 7 , a, r, and s are as defined above.
  • the commercially available amino acid esters EE can be coupled with a fatty acid of the formula D using a coupling agent such as EDCI or HATU, followed by alkaline hydrolysis of the methyl ester to afford compounds of the formula FF.
  • Compounds of the formula FF can be coupled with the commercially available BOC-amino acid conjugates GG using a coupling agent such as EDCI or HATU.
  • the BOC group can be removed by treatment with acids such as TFA or HCl to afford compounds of the formula HH which can then be coupled with compound A to afford compounds of the formula II.
  • Niacin has been reported to increase serum levels of HDL to LDL cholesterol in vivo. Similarly, niacin has been reported to increase the secretion of ApoAl (Jin, F- Y. et al. Arterioscler. Thromb. Vase. Biol. 1997, 17 (10), 2020-2028) while inhibiting the secretion of ApoB (Jin, F- Y. et al. Arterioscler. Thromb. Vase. Biol. 1999, 19, 1051-1059) in the media supernatants of HepG2 cultures. Independently, DHA has been demonstrated to lower ApoB as well (Pan, M. et al. J. Clin. Invest.
  • the secretion of ApoB from HepG2 cells possesses utility as a cell based read-out for niacin-DHA conjugates, as well as conjugates of same.
  • HepG2 cells are seeded at 10,000 cells per well in 96 well plates. After adhering overnight, growth media (10% FBS in DMEM) is removed and cells are serum starved for 24 hours in DMEM containing 0.1% fatty acid free bovine serum albumin (BSA, Sigma). Cells are then treated with a compound. Niacin at 5 mM is used as a positive control. All treatments are performed in triplicate. Simultaneous with compound treatment, ApoB secretion is stimulated with addition of 0.1 oleate complexed to fatty acid free BSA in a 5: 1 molar ratio. Incubation with a compound and oleate is conducted for 24 hours.
  • growth media (10% FBS in DMEM) is removed and cells are serum starved for 24 hours in DMEM containing 0.1% fatty acid free bovine serum albumin (BSA, Sigma). Cells are then treated with a compound. Niacin at 5 mM is used as a positive control. All treatments are performed in triplicate
  • IC 50 concentration at which 50% of ApoB secretion is inhibited
  • Graph Pad Prism® 4 parameter-fit inhibition curve model
  • the fatty acid niacin conjugate 1-7 was evaluated in HepG2 cells at 3 concentrations (50, 100 and 200 ⁇ ). The level of ApoB secretion was compared to that of niacin, evaluated at 5 mM concentration. Compared to niacin, the fatty acid niacin conjugate 1-7 showed significant inhibition of ApoB at a much lower drug concentration.
  • Example 2
  • HepG2 cells were seeded at 20,000 cells per well in 96 well plates. After adhering overnight, growth media (10% FBS in DMEM) was removed and cells were serum starved for 24 hours in DMEM containing 1% fatty acid free bovine serum albumin (BSA, Sigma). Cells were then treated with one of four substances at a final concentration of 50 ⁇ in 1% BSA or 0.1% oleate complexed to fatty acid free BSA in a 5: 1 molar ratio (the four substances were compound 1-7, compound 1-8, a combination of free niacin and free DHA, or a combination of free niacin and free EPA).
  • growth media (10% FBS in DMEM) was removed and cells were serum starved for 24 hours in DMEM containing 1% fatty acid free bovine serum albumin (BSA, Sigma). Cells were then treated with one of four substances at a final concentration of 50 ⁇ in 1% BSA or 0.1% oleate complexed to fatty acid
  • Atorvastatin 0.0015% w/w in diet (to achieve about 20% reduction in plasma
  • EDTA plasma was collected in weeks -4, 0, 2 and 4 weeks. Plasma cholesterol, plasma triglyceride levels and lipoprotein profiles were assayed immediately in fresh plasma.
  • Figures 4 and 5 show the plasma cholesterol and triglyceride levels respectively after 4 weeks of treatment.
  • Figure 5 shows the corresponding plasma triglyceride levels in the same treatment groups after 4 weeks of treatment.
  • ApoE*3 Leiden mice treated with compound 1-8 showed a significant reduction in triglycerides after 4 weeks of treatment.
  • ApoE*3 Leiden mice treated with atorvastatin failed to show a statistically significant change triglyceride level after 4 weeks of treatment.
  • ApoE*3 Leiden mice treated with a combination of compound 1-8 and atorvastatin showed a significant reduction in plasma triglycerides after 4 weeks of treatment.
  • Healthy human volunteers were divided into 4 treatment groups.
  • All subjects were given an NIH high fat breakfast in order to induce an elevated level of triglycerides (In a typical NIH high fat breakfast, 450 calories are derived from fat).
  • Compound 1-8 was then administered as a single oral dose at the three indicated doses at three different time points: immediately following the high fat meal, 2 hours following the high fat meal and 4 hours following the high fat meal. At each of the time points, plasma triglyceride levels were determined according to standard protocols.
  • the objective of this example is to determine if 1-8, a representative compound of the present invention, can abrogate the development of hepatic steatosis induced by oral administration of the MTP inhibitor Lomitapide for 7 days in normal mice.
  • mice Male C57BL/6 mice were acclimated to the high fat cholesterol diet (D13093001; 1% cholesterol, 15% cacao butter, 40.5%> sucrose and 1% corn oil (Research Diets, Inc. New Brunswick, NJ) upon arrival at CRO facility.
  • the test diet containing the compound (1-8) sufficient for approx. 3 kg of diet i.e. 25 g of 1-8 from the invention
  • mice were randomized into each of the 3 treatment groups (1-3) and acclimated on the appropriate diet (D13093001 or D13093002) as indicated in Table 1.
  • mice received an oral gavage dose of vehicle.
  • the baseline blood samples were collected from each mouse 90 minutes after the vehicle dose and stored as plasma.
  • Mice were dosed once daily (QD) with Lomitapide or vehicle by oral gavage beginning on day 1 (Table 1).
  • the dosing regimen was of 7 days duration. Plasma and tissue was collected as described.
  • OCT VWR International
  • the intestine was cut mid-way in the jejunum to generate two equal parts one containing the jejunum/ileum, the other containing the jejunum/duodenum. Each piece was weighed and snap frozen in separate 50 mL conical tubes. Plasma was snap frozen and all plasma and tissue samples stored at -80°C.
  • Observations were recorded at least twice daily and at each sample collection time point. The presence or absence of any clinical abnormalities was recorded. Body weights were recorded on Day -7, and daily on Day -1 through Day 7(AM). Interim blood samples were collected and a terminal blood sample was collected on Day 7 by intracardiac puncture following anesthetization with C02. Each whole blood sample was transferred into tubes containing sodium heparin anticoagulant and placed on ice until processing. Each whole blood sample was centrifuged at 2200 x g for 10 minutes at 5°C ⁇ 3°C to isolate plasma. The plasma from the pre-treatment, interim, and terminal blood samples was transferred to individual wells in a 96-well plate format. All plasma samples were immediately placed in dry ice until storage at nominally -70°C.
  • liver and small intestine was collected from each animal. Extraneous connective tissue was removed and the liver was rinsed with saline, gently blotted dry, and weighed. The left lobe of the liver was cut into two sections (approx. 1/3 and 2/3), weighed, and transferred to screw-cap tubes, and each snap- frozen in liquid nitrogen separately. The right lobe was weighed and snap-frozen in OCT for use in immunohistochemistry. The remainder of the liver was weighed and snap-frozen in a 50mL polypropylene conical tube.
  • the small intestine was excised at the junction of the cecum and stomach and was emptied of all contents, rinsed with saline, gently blotted dry, and weighed.
  • the intestine was cut mid-way in the jejunum to generate two equal parts, one containing the jejunum/ileum and the other containing the jejunum/duodenum. Each segment was weighed, transferred to a separate 50mL polypropylene conical tube, and snap-frozen in liquid nitrogen.
  • Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc 2 0 (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH 2 P0 4 (20 mL).
  • aqueous layer was washed with a 1 : 1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc.
  • the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44 %).
  • nicotinic acid (246 mg, 2.0 mmol) was taken up in CH3CN (10 mL) along with tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (503 mg, 2.0 mmol), EDCI (422 mg, 2.2 mmol).
  • the resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc.
  • the organic layer was washed with dilute aqueous NaHC0 3 , brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • tert- utyl 2-(2-(2-(nicotinamido)ethyl)disulfanyl)ethylcarbamate 200 mg, 0.56 mmol was taken up in 25% TFA in CH 2 C1 2 solution (5 mL) and allowed to stand at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-(2-aminoethyl)disulfanyl)ethyl)nicotinamide.
  • tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH 3 CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHC0 3 , brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • tert- utyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate 140 mg, 0.453 mmol was taken up in 25% TFA in CH 2 CI 2 (10 mL). The reaction mixture was allowed to stand at room temperature for 2 h and then concentrated under reduced pressure to afford the TFA salt of N- (2-(2-aminoethoxy)ethyl)nicotinamide.
  • tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate 400 mg, 1.84 mmol was taken up in CH3CN (10 mL) along with nicotinic acid (227 mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHC0 3 , brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • tert-Butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (90 mg, 0.279 mmol) was taken up in a 25% TFA in CH 2 C1 2 solution (5 mL) and allowed to stand at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the TFA salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)nicotinamide.
  • H-Lysine-(BOC)-OMe hydrochloride 500 mg, 1.68 mmol was taken up in CH 3 CN (10 mL) along with nicotinic acid (207 mg, 1.68 mmol), EDCI (354 mg, 1.85 mmol) and DIEA (0.90 mL). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with dilute aqueous NaHC0 3 , brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH 2 C1 2 ) afforded (5)-methyl 6-(tert-butoxycarbonyl)-2- (nicotinamido)hexanoate (520 mg, 85%).
  • H-Lysine-(BOC)-OMe hydrochloride 500 mg, 1.68 mmol was taken up in 25 mL of CH 3 CN along with (5Z,8Z,1 lZ,14Z,17Z)-eicosa-5,8,l 1,14,17-pentaenoic acid (EPA, 509 mg, 1.68 mmol), HATU (702 mg, 1.85 mmol) and DIEA (880 ⁇ , 5.04 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc (70 mL) and washed with brine (20 mL). The organic layer was dried (Na 2 S0 4 ) and concentrated under reduced pressure.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des conjugués d'acides gras et de niacine ; des compositions contenant une quantité efficace d'un conjugué d'acides gras et de niacine ; des méthodes de traitement ou de prévention d'une maladie métabolique impliquant l'administration d'une quantité efficace d'un conjugué d'acides gras et de niacine et des méthodes de traitement ou de prévention d'une maladie métabolique impliquant l'administration d'une quantité efficace d'un conjugué d'acides gras et de niacine et d'un autre agent thérapeutique.
EP14735304.9A 2013-01-07 2014-01-07 Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies Withdrawn EP2941252A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201361749734P 2013-01-07 2013-01-07
US201361911292P 2013-12-03 2013-12-03
PCT/US2014/010515 WO2014107730A2 (fr) 2013-01-07 2014-01-07 Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies

Publications (2)

Publication Number Publication Date
EP2941252A2 true EP2941252A2 (fr) 2015-11-11
EP2941252A4 EP2941252A4 (fr) 2016-07-13

Family

ID=51062564

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14735304.9A Withdrawn EP2941252A4 (fr) 2013-01-07 2014-01-07 Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies

Country Status (5)

Country Link
US (1) US20150352094A1 (fr)
EP (1) EP2941252A4 (fr)
AU (1) AU2014203872A1 (fr)
CA (1) CA2896776A1 (fr)
WO (1) WO2014107730A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110833620A (zh) * 2018-08-15 2020-02-25 王镕 血管紧张素转化酶抑制剂在防治自身免疫性疾病及相应的并发症中的用途

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2012DN02661A (fr) 2009-09-01 2015-09-11 Catabasis Pharmaceuticals Inc
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
CN107243078A (zh) * 2012-05-25 2017-10-13 克塔巴西斯制药有限公司 使前蛋白转化酶枯草溶菌素/kexin 9型（pcsk9）减少的方法
US20160279161A1 (en) * 2013-11-14 2016-09-29 Newsouth Innovation Pty Limited Senescence and senescence associated secretory phenotype
MA41031A (fr) 2014-11-26 2017-10-03 Catabasis Pharmaceuticals Inc Conjugués cystéamine-acide gras et leur utilisation comme activateurs de l'autophagie
US10603334B2 (en) 2015-04-28 2020-03-31 NewSouth Innovation Pty. Limited Targeting NAD+ to treat chemotherapy and radiotherapy induced cognitive impairment, neuropathies and inactivity
WO2017106630A1 (fr) * 2015-12-18 2017-06-22 The General Hospital Corporation Polymères polyacétal, conjugués, particules et utilisations associées
AU2020380404A1 (en) * 2019-11-08 2022-06-09 Retina Foundation Of The Southwest Compounds and implants for treating ocular disorders
CN112047998B (zh) * 2020-09-07 2024-01-09 上海阿达玛斯试剂有限公司 一种培哚普利的制备方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5219847A (en) * 1989-06-12 1993-06-15 Shiseido Company, Ltd. Antipruritic composition
CA2048395A1 (fr) * 1990-08-23 1992-02-24 Henry Y. Pan Methode de traitement ou de prevention de l'apparition d'une hyperlipoproteinemie de type iii.
AU2002953255A0 (en) * 2002-12-11 2003-01-02 Cytopia Research Pty Ltd Protein kinase inhibitors
IN2012DN02661A (fr) * 2009-09-01 2015-09-11 Catabasis Pharmaceuticals Inc
CN103648490A (zh) * 2011-03-18 2014-03-19 凯特贝希制药公司 胞内酶用于释放共价连接的生物活性物的用途
US20120252810A1 (en) * 2011-04-04 2012-10-04 Catabasis Pharmaceuticals, Inc. Fatty acid non-flushing niacin derivatives and their uses
CN102532114B (zh) * 2011-12-19 2016-08-03 中山大学 烟酸衍生物,其制备方法及其药物组合物
CN107243078A (zh) * 2012-05-25 2017-10-13 克塔巴西斯制药有限公司 使前蛋白转化酶枯草溶菌素/kexin 9型（pcsk9）减少的方法
WO2015073901A1 (fr) * 2013-11-15 2015-05-21 Catabasis Pharmaceuticals, Inc. Conjugués acide gras niacine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110833620A (zh) * 2018-08-15 2020-02-25 王镕 血管紧张素转化酶抑制剂在防治自身免疫性疾病及相应的并发症中的用途

Also Published As

Publication number Publication date
EP2941252A4 (fr) 2016-07-13
CA2896776A1 (fr) 2014-07-10
US20150352094A1 (en) 2015-12-10
WO2014107730A3 (fr) 2014-08-21
AU2014203872A1 (en) 2015-07-09
WO2014107730A2 (fr) 2014-07-10

Similar Documents

Publication Publication Date Title
EP2941252A2 (fr) Utilisation de conjugués d'acides gras et de niacine en vue du traitement de maladies
EP2473045B1 (fr) Conjugués acides gras niacine et leurs utilisations
WO2013177536A2 (fr) Méthodes de diminution de la proprotéine convertase subtilisine/kexine de type 9 (pcsk9)
WO2011106688A1 (fr) Conjugués de bis-acide gras et leurs utilisations
WO2012115695A1 (fr) Conjugués de bis-acides gras et leurs utilisations
WO2013166176A1 (fr) Conjugués d'acide gras de statine et d'agonistes de fxr ; compositions et procédés d'utilisation
US20160287712A1 (en) Fatty acid niacin conjugates
WO2011044139A1 (fr) Dérivés d'acifran et d'acides gras et leurs utilisations
US20120252810A1 (en) Fatty acid non-flushing niacin derivatives and their uses
WO2011044136A1 (fr) Dérivés d'acipimox d'acide gras et leurs utilisations
USRE46608E1 (en) Fatty acid niacin conjugates and their uses

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150724

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20160613

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/541 20060101AFI20160607BHEP

Ipc: A61P 3/06 20060101ALI20160607BHEP

Ipc: A61P 3/10 20060101ALI20160607BHEP

Ipc: A61P 3/00 20060101ALI20160607BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20160825